Arrhythmias are abnormal rhythms of the heart and cause the heart to pump less effectively. At this time, electro-biochemical properties on local regions of cardiac muscle are changed due to a variety of causes, and thus abnormal cardiac impulse formation or impulse propagation occurs.
The shape and duration of cardiac action potentials vary depending on the region of the heart where they are recorded. These regional differences result, in part, from the differential expression of K+ channel genes within the myocardium (Sanguinetti and Keating. Role of delayed rectifier potassium channels in cardiac repolarization and arrhythmias. News Physiol Sci 1997, 12:152-157).
All antiarrhythmic drugs influence the movement of ions in cardiac muscle to exhibit antiarrhythmic effects. Accordingly, antiarrhythmic drugs are commonly divided into the following classes according to the kinds of the moving ions: I (sodium channel blockers), II (β-adrenergic receptor blockers), III (potassium channel blockers), IV (calcium channel blockers), etc. (Katz A M. Selectivity and toxicity of antiarrhythmic drugs: molecular interactions with ion channels. AM J Med 1998, 104: 179-195). A major obstacle to the widespread use of drugs to manage cardiac arrhythmias has been a relatively high incidence of extracardiac side effects. With increasingly sophisticated drug development, it is possible to develop drugs that show significantly reduced extracardiac side effects due to the improved tissue-specificity. However, cardiac side effects, which often arise as a direct consequence of drugs' antiarrhythmic mechanisms, have been very difficult to be circumvented. Common cardiac side effects of antiarrhythmic drugs include depressed contractile performance, bradycardia, altered efficacy of pacing and defibrillating devices, and the occurrence of new arrhythmias or increased occurrence of arrhythmias (proarrhythmia) (Roden D M. Mechanism and management of proarrhythmia. Am J Cardiol 1998, 82: 491-571).
Antiarrhythmic drugs regulating action potential durations, which are important in controlling heart rate, have already been developed. However, these drugs also produce various side effects as described above, which limits their clinical applications.
Therefore, an ideal antiarrhythmic drug with fewer side effects must act only on cardiac myocytes showing abnormal excitability (or cells having abnormal heart rate), or arrhythmia-occurring tissues (e.g., atrial myocytes, ventricular myocytes, Purkinje fibers, etc). However, drugs satisfying the above requirements have not yet been developed. In order to develop a novel drug with few or no side effects, molecular biological knowledge for the targets of antiarrhythmic drugs (such as ion channels) must be accompanied. For example, the ion channel which selectively expresses in arrhythmogenic tissues, is one of the targets of ideal antiarrhythmic drugs. Accordingly, approaches by the combination of molecular biological cloning techniques and electro-pharmacological techniques will make it possible to develop new ideal antiarrhythmic drugs.
It is well known that various K+ channels regulate action potential durations and K+ channel genes differentially express depending on the regions of the heart. K+ channels represent the most diverse class of ion channels in heart. K+ currents in the myocardium can be classified into two categories: 1) inward K+ currents such as IK1 (inward rectifying K+ current), IKAch (acetylcholine-activated K+ current), and IKATP (ATP-sensitive K+ current); and 2) voltage-gated K+ (Kv) currents. The inward K+ currents regulate resting membrane potential, whereas the Kv currents control action potential duration.
The cardiac Kv currents are divided into Ito, IKP, IKR, IKUR, and IKS in accordance with their electrophysiological characteristics. Ito current, a transient outward K+ current, is activated immediately after membrane depolarization, and then becomes inactive rapidly. Therefore, Ito is of importance in phase 1 of action potential. IKP current, a plateau K+ current, becomes active only during membrane depolarization, and is a kind of delayed outward K+ current with an intermediate rate of activation. IKR current, a rapidly activating delayed rectifier K+ current, is of importance in phase 2 of action potential. IKUR current, an ultra-rapidly activating delayed rectifier K+ current, is also of importance in phase 2 of action potential. IKS current, a slow-activating delayed rectifier K+ current, takes a few seconds to become active completely, and is of importance in final repolarization of phase 3 of action potential (Roden and George, The cardiac ion channel: relevance to management of arrhythmias. Annu Rev Med 1999, 47: 138-148). These Kv channels contribute to cell repolarization and regulate the action potential duration. Clinically, it is known that the repolarization disorders in the damaged tissues result in cardiac arrhythmias. Accordingly, Kv channels become major targets for the treatment of arrhythmias. In practical use, it is known that antiarrhythmic drugs such as quinidine, verapamil, nifedipine, sotalol, amiodarone, flecainide, and cropyrium interact with the Kv channels (Katz A M. Selectivity and toxicity of antiarrhythmic drugs: molecular interactions with ion channels. Am J Med 1998, 104: 174-195). However, these drugs are known to have various side effects due to their lack of selectivity for ion channels. Accordingly, there remains a need to develop a novel drug acting specifically on the ion channel in extraordinarily hyperexcitable tissues.
The first cloned K+ channel gene, Shaker, was obtained using the techniques of Drosophila genetics and DNA manipulation. cDNAs of mammalian Kv channel reported until now are divided into nine subfamilies, Kv1˜Kv9. Among them, Kv1 subfamily is the most diverse one, and includes at least eight subclasses, Kv1.1˜Kv1.8 (Grissner S. Potassium channels still hot, TiPS 1997, 18: 347-350). Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv2.1, Kv4.2 and Kv4.3 of Kv channel genes have been cloned from cardiac tissue (Deal, et al., Molecular physiology ofcardiac potassium channels. Physiol Rev 1996, 76: 49-67). Main Kv channel genes expressed in human heart are hKv1.4, hKv1.5, hKv4.3 and HERG genes. All these genes are highly expressed in both atrium and ventricle, and in particular, the hKv1.5 gene is preferentially expressed in human atrium. The hKv1.5 is known to have the same electrophysiological and pharmacological properties as IKUR, a current specific in human atrium (Fedid, et al., The 1997 Stevenson Award Lecture, Cardiac K+ channel gating: cloned delayed rectifier mechanisms and drug modulation. Can J Physiol Pharmacol 1998, 76: 77-89). Development of highly selective blockers for the hKv1.5 channel will lead to an ideal drug for the treatment of atrial fibrillations.
The present inventors have earnestly and intensively searched to develop a selective blocker for the hKv1.5 channel which is preferentially expressed in human atrium, and as a result, have found that chelidonine and derivatives thereof inhibit hKv1.5 channel currents and IKUR currents in human atrial myocytes. In addition, they also found that the prolonging effects of action potential duration are proportional to the heart rate.
Therefore, it is an object of the present invention to provide a composition comprising chelidonine or derivatives thereof which exhibit excellent K+ channel blocking effect and antiarrhythmic effect, with pharmaceutically acceptable carriers.